Kobata T, Takasaki K, Asahara H, Hong N M, Masuko-Hongo K, Kato T, Hirose S, Shirai T, Kayagaki N, Yagita H, Okumura K, Nishioka K
Rheumatology Program, St Marianna University School of Medicine, Kawasaki, Japan.
Immunology. 1997 Oct;92(2):206-13. doi: 10.1046/j.1365-2567.1997.00347.x.
Fas (CD95) ligand (L) is a death factor that binds to its receptor, Fas, and induces apoptotic cell death, a crucial process in immunological tolerance. gld (generalized lymphoproliferative disorder) mice, which have a point mutation in the FasL gene, develop spontaneous systemic autoimmune syndromes characterized by hypergammaglobulinaemia and lymphoid hyperplasia owing to accumulation of abnormal B220+ CD3+ cells. Transplantation of wild-type (wt) bone marrow cells into old gld mice on the same strain background results in normalization of autoimmune syndromes. We characterized the cellular mechanisms (functionally and histologically) of the above phenomena in gld mice after bone marrow transplantation (BMT) to determine the role of apoptosis via Fas/FasL interactions in inducing and maintaining self-tolerance in vivo. Activated splenocytes from wt and BMT (wt to gld) mice showed significant cytotoxic activity against Fas transfectant cells while those from BMT (gld to gld) mice did not. Cells in the thymus, spleen and lymph nodes of gld mice uniformly upregulated Fas expression and were sensitive to Fas-mediated apoptosis compared with those in wt mice. Cells sensitive to Fas-mediated apoptosis in gld mice resided not only among abnormal B220+ CD3+ cells but also among conventional lymphocytes. More importantly, histological analysis revealed that cells in the spleen, lymph nodes and thymus frequently underwent apoptosis with infiltration of FasL+ cells in BMT (wt to gld) mice compared with BMT (gld to gld) mice. Our results indicated that apoptosis via Fas/FasL interactions can directly eliminate pathogenic cells responsible for autoimmunity in the periphery and possibly in the thymus in vivo.
Fas(CD95)配体(L)是一种死亡因子,它与其受体Fas结合并诱导凋亡性细胞死亡,这是免疫耐受中的一个关键过程。gld(全身性淋巴增殖性疾病)小鼠的FasL基因存在点突变,由于异常B220 + CD3 +细胞的积累,会出现以高球蛋白血症和淋巴样增生为特征的自发性全身性自身免疫综合征。将野生型(wt)骨髓细胞移植到相同品系背景的老龄gld小鼠中可使自身免疫综合征恢复正常。我们对骨髓移植(BMT)后gld小鼠上述现象的细胞机制(功能和组织学)进行了表征,以确定通过Fas/FasL相互作用的凋亡在体内诱导和维持自身耐受中的作用。来自wt和BMT(wt至gld)小鼠的活化脾细胞对Fas转染细胞显示出显著的细胞毒性活性,而来自BMT(gld至gld)小鼠的活化脾细胞则没有。与wt小鼠相比,gld小鼠胸腺、脾脏和淋巴结中的细胞均上调了Fas表达,并且对Fas介导的凋亡敏感。gld小鼠中对Fas介导的凋亡敏感的细胞不仅存在于异常B220 + CD3 +细胞中,也存在于传统淋巴细胞中。更重要的是,组织学分析显示,与BMT(gld至gld)小鼠相比,BMT(wt至gld)小鼠的脾脏、淋巴结和胸腺中的细胞频繁发生凋亡,并伴有FasL +细胞浸润。我们的结果表明,通过Fas/FasL相互作用的凋亡可以直接消除体内外周以及可能胸腺中负责自身免疫的致病细胞。